Regulation of the Cell Fate Program During Drosophila Germline Stem Cell Differentiation and Meiotic Initiation
Year: 2024
Type: dissertation
Abstract: Germ cells act as the carriers of genetic information and are vital in the propagation of a sexually reproducing species. Furthermore, oocytes establish early embryonic development by containing nearly all necessary components. If oocyte development goes awry during germ cell differentiation, fertility of the individual or the fitness of the offspring will be impaired. Thus, to ensure the continuation of a species across generations, the development of oocytes must be finely regulated, and the stability of the genome maintained. However, there exist gaps in our understanding of oocyte development and genome maintenance. In this thesis, I investigate two sequential and essential steps in female germline development: the differentiation of germline stem cells (GSCs) into mitotically dividing cysts; and then the transition of these mitotic cysts into meiosis. For the first step, I found mitochondrial remodelling essential in the differentiation of GSCs. Failure to remodel the inner mitochondrial membrane (IMM) induces endoplasmic reticulum (ER) bilayer stress and activates the integrated stress response (ISR) through the Protein kinase R (PKR)-like ER Kinase (PERK). This causes an attenuation of global protein synthesis, precocious entry into meiosis and cell death ultimately resulting in sterility. For the second step, I discovered a previously unreported role for the RNA-binding protein (RBP) Ataxin-2 (Atx2) in the transition from mitosis to meiosis. I show that Atx2 is critical for promoting the timely entry into premeiotic DNA replication, the first step of meiosis, through controlling the levels of the cell cycle regulator Dacapo (Dap). Failure to initiate meiosis in a timely manner resulted in the loss of oocyte genome stability and infertility. Additionally, following a transcriptome-wide analysis of premeiotic and meiotic germ cells, I found that Atx2 regulates genes involved in diverse aspects of female germline development including subsequent meiotic processes. Thus, I have found additional regulators of germline differentiation and the subsequent transition from mitosis to meiosis in Drosophila.
Source: TSpace (University of Toronto)
Author: Monteiro, Vernon Leander
Institution: University of Toronto
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132907829